Background

Central histamine (HA) signaling modulates diverse cortical and subcortical circuits throughout the brain, including the nucleus accumbens (NAc). The NAc, a key striatal subregion directing reward-related behavior, expresses diverse HA receptor subtypes that elicit cellular and synaptic plasticity. However, the neuromodulatory capacity of HA within interneuron microcircuits in the NAc remains unknown.

Methods

We combined electrophysiology, pharmacology, voltammetry, and optogenetics in male transgenic reporter mice to determine how HA influences microcircuit motifs controlled by parvalbumin-expressing fast-spiking interneurons (PV-INs) and tonically active cholinergic interneurons (CINs) in the NAc shell.

Results

HA enhanced CIN output through an H₂ receptor (H₂R)–dependent effector pathway requiring Ca²⁺-activated small-conductance K⁺ channels, with a small but discernible contribution from H₁Rs and synaptic H₃Rs. While PV-IN excitability was unaffected by HA, presynaptic H₃Rs decreased feedforward drive onto PV-INs via AC-cAMP-PKA (adenylyl cyclase–cyclic adenosine monophosphate–protein kinase A) signaling. H₃R-dependent plasticity was differentially expressed at mediodorsal thalamus and prefrontal cortex synapses onto PV-INs, with mediodorsal thalamus synapses undergoing HA-induced long-term depression. These effects triggered downstream shifts in PV-IN- and CIN-controlled microcircuits, including near-complete collapse of mediodorsal thalamus–evoked feedforward inhibition and increased mesoaccumbens dopamine release.

Conclusions

HA targets H₁R, H₂R, and H₃Rs in the NAc shell to engage synapse- and cell type–specific mechanisms that bidirectionally regulate PV-IN and CIN microcircuit activity. These findings extend the current conceptual framework of HA signaling and offer critical insight into the modulatory potential of HA in the brain.

中文翻译：

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累积组胺信号传导离散中间神经元微电路

 背景

中枢组胺 (HA) 信号调节整个大脑的不同皮质和皮质下回路，包括伏隔核 (NAc)。 NAc 是指导奖赏相关行为的关键纹状体亚区，表达多种HA 受体亚型，引发细胞和突触可塑性。然而，NAc 中神经元微电路内 HA 的神经调节能力仍然未知。

 方法

我们在雄性转基因报告小鼠中结合了电生理学、药理学、伏安法和光遗传学，以确定 HA 如何影响 NAc 壳中表达小清蛋白的快速尖峰中间神经元 (PV-IN) 和强直活性胆碱能中间神经元 (CIN) 控制的微电路基序。

 结果

HA 通过 H ₂受体 (H ₂ R) 依赖性效应途径增强 CIN 输出，该途径需要 Ca ²⁺激活的小电导 K ⁺通道，其中 H ₁ R 和突触 H ₃ R 的贡献虽小但可辨别。虽然 PV-IN 兴奋性不受 HA 影响，但突触前 H ₃ Rs 通过 AC-cAMP-PKA（腺苷酸环化酶 - 环磷酸腺苷 - 蛋白激酶 A）信号传导减少了对 PV-IN 的前馈驱动。 H ₃ R依赖性可塑性在内侧丘脑和前额皮质突触PV-IN上有差异表达，内侧丘脑突触经历HA诱导的长期抑郁。这些效应触发了 PV-IN 和 CIN 控制的微电路的下游变化，包括丘脑内侧丘脑几乎完全崩溃引起的前馈抑制和中伏隔多巴胺释放增加。

 结论

HA 靶向 NAc 壳中的 H ₁ R、H ₂ R 和 H ₃ R，以参与双向调节 PV-IN 和 CIN 微电路活动的突触和细胞类型特异性机制。这些发现扩展了当前 HA 信号传导的概念框架，并为大脑中 HA 的调节潜力提供了重要的见解。